Parkinson's disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by protein ubiquitination. Although we do not observe major defects in mitochondria of mutant neuropeptidergic neurons, we do find an excess of endoplasmic reticulum-mitochondrial contacts. These excessive contact sites cause abnormal lipid trafficking that depletes phosphatidylserine from the endoplasmic reticulum (ER) and disrupts the production of neuropeptide-containing vesicles. Feeding mutant animals phosphatidylserine rescues neuropeptidergic vesicle production and acutely restores normal sleep patterns in mutant animals. Hence, sleep patterns and circadian disturbances in Parkinson's disease models are explained by excessive ER-mitochondrial contacts, and blocking their formation or increasing phosphatidylserine levels rescues the defects in vivo.

Parkinson’s disease–causing mutations in PINK1 yield mitochondrial defects including inefficient electron transport between complex I and ubiquinone. Vos et al. show that genetic and pharmacological inhibition of fatty acid synthase bypass these complex I defects in fly, mouse, and human Parkinson’s disease models.

Circumferential skin creases (CSC-KT) is a rare polymalformative syndrome characterised by intellectual disability associated with skin creases on the limbs, and very characteristic craniofacial malformations. Previously, heterozygous and homozygous mutations in MAPRE2 were found to be causal for this disease. MAPRE2 encodes for a member of evolutionary conserved microtubule plus end tracking proteins, the end binding (EB) family. Unlike MAPRE1 and MAPRE3, MAPRE2 is not required for the persistent growth and stabilization of microtubules, but plays a role in other cellular processes such as mitotic progression and regulation of cell adhesion. The mutations identified in MAPRE2 all reside within the calponin homology domain, responsible to track and interact with the plus-end tip of growing microtubules, and previous data showed that altered dosage of MAPRE2 resulted in abnormal branchial arch patterning in zebrafish. In this study, we developed patient derived induced pluripotent stem cell lines for MAPRE2, together with isogenic controls, using CRISPR/Cas9 technology, and differentiated them towards neural crest cells with cranial identity. We show that changes in MAPRE2 lead to alterations in neural crest migration in vitro but also in vivo, following xenotransplantation of neural crest progenitors into developing chicken embryos. In addition, we provide evidence that changes in focal adhesion might underlie the altered cell motility of the MAPRE2 mutant cranial neural crest cells. Our data provide evidence that MAPRE2 is involved in cellular migration of cranial neural crest and offers critical insights into the mechanism underlying the craniofacial dysmorphisms and cleft palate present in CSC-KT patients. This adds the CSC-KT disorder to the growing list of neurocristopathies.

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Background Tau tangles are present in the brains of Alzheimer diseased (AD) patients and strategies that remove Tau oligomers and Tau tangles are tested in clinical trials. These anti‐Tau drugs may keep misfolded Tau from spreading and damaging additional neurons, but they may be inefficient at targeting soluble Tau early in the disease before tangles are formed and thus be relatively late to spare cognitive defects. Our research is therefore refreshing as it may tackle early Tau induced dysfunction. We have shown in Drosophila that the overexpression of the chaperone Hsc70‐4 promotes endosomal microautophagy at presynapses and regulates the turnover of synaptic proteins harboring pentapeptide motifs, biochemically related to the KFERQ sequence (Uytterhoeven, 2015). Intriguingly, Tau harbors two such motifs. Method We tested if increasing endosomal microautophagy by overexpressing Hsc70‐4 has an effect on Tau‐mediated synaptic defects . Result Indeed, increasing microautophagy reduces presynaptic Tau levels and presynaptic vesicle sequestrations at presynapses, two phenotypes previously shown by our lab to appear after expressing pathogenic Tau in the fly nervous system (Zhou, 2017 and McInnes, 2018). In addition, via lentiviral‐mediated overexpression of HSPA8, the human homologue of Hsc70‐4, we are able to increase HSPA8 regulated autophagy in human neurons. Conclusion Together, our work provides important molecular insight into the contribution of Hsc70‐4/HSPA8 regulated autophagy on AD disease onset and progression and may contribute to the development of methods and treatments to alleviate the defects in dementia.